Mutant BCL2 Co-Operates with CBFβ/PEBP2β-MYH11 to Promote Expansion of Leukemia Initiating Cells with a Predominantly Pro-Apoptotic Mechanism Via Recruitment of Ras-GTP In a Mouse Model of Progressive Acute Myeloid Leukemia

• Published in: Blood 2010-11, Vol.116 (21), p.1050-1050
• Main Authors: Omidvar, Nader, Pogam, Carole Le, Beurlet, Stephanie, Noguera, Maria-Elena, Janin, Ann, Kogan, Scott C., Weissman, Irving L., Pla, Marika, Chomienne, Christine, Padua, Rose Ann
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.1050.1050

Abstract 1050 Mutations and translocation of the core binding factor complexes frequently co-operate with other lesions in Acute Myeloid Leukemia (AML). In order to study the molecular mechanisms and develop therapeutic platforms we have developed highly penetrant and tractable mouse models. We crossed single transgenic mice that express the human (h)BCL2 or NRASD12 under the control of the myeloid promoter MRP8 with single transgenic mice that express the protein fusion CBFβ/PEBP2β-MYH11 (Inv16) under the same promoter. Whereas single transgenic mice have a normal lifespan, the double transgenic mice develop rapid and fatal hematologic disease. The NRASD12/Inv16 mice are already known to develop strong features of dysmyelopoiesis, developing severe thrombopenia and anemia associated with leucocytosis (Kogan SC, et al. PNAS USA 95:11863-11868). Here within marrow and spleen cells we find abnormal eosinophils with Charcot-Leydan crystals associated with an increase of myeloid blasts, features that are found in human AML4 with eosinophilia. The hBCL2/Inv16 mice develop anemia and leucopenia, with greater than 30% bone marrow blast cells associated with enlarged infiltrated liver and spleens. Consequently hBCL2/Inv16 animals demonstrated significantly reduced survival as compared to litter mate controls (median 65 days; p